It has already been revealed that coumarin derivatives, ice., compounds which have a coumarin skeleton as a core structure, and in which the skeleton is derivatized at various positions, have different pharmacological effects depending on the position at which a chemical modification occurs (Non-patent document 31). For example, warfarin, which has antithrombogenic activity, is well known as a drug having a coumarin skeleton (Non-patent document 1). Furthermore, coumarin derivatives which exert antitumor activity by acting on various different target proteins, or coumarin derivatives which inhibit proteins associated with antitumor activity have been obtained by chemical modification at different positions of the core structure.
A coumarin derivative that exerts antitumor activity by inhibiting steroid sulfatase has been reported (Non-patent documents 2 to 6). This is currently in clinical testing. This compound forms a cycloalkyl group at the 3- and 4-positions of the coumarin skeleton, and has a sulfamate group at the 7-position. Its application to breast cancer is being considered from the viewpoint of pharmacological action.
Furthermore, as for coumarin derivatives which exert antitumor activity through binding to the estrogen receptor, a group of compounds having a characteristic substituent at the 4-position have been reported. Specifically, there have been reported a group of compounds having an arylalkyl group at the 4-position and having substituents at the 3- and 7-positions (Patent document 1), and a group of compounds in which a phenyl group is directly bound to the skeleton at the 4-position, and which have a phenoxy group at the 3-position (Patent document 2).
Also, as for a coumarin derivative exhibiting Raf inhibitory activity and exhibiting antitumor activity in cells, a compound having a 6-pyrazinyloxy group at the 7-position has been reported (Patent document 5).
In addition, known are several coumarin derivatives whose target proteins are unknown, and which are reported to exhibit antitumor activity. These include a group of compounds derived from natural sources (Non-patent documents 7 to 12), and a group of new compounds obtained by chemical synthesis (Non-patent documents 13 to 23, 32 to 34). As for the new compounds obtained by chemical synthesis, there have been reported, for example: a compound having alkoxy groups at the 5-, 6- and 7-positions of the coumarin skeleton (Non-patent document 13); a compound having an alkoxy group only at the 7-position of the coumarin skeleton (Non-patent document 14); a compound having an enone functional group at the 6- or 7-position of the coumarin skeleton (Non-patent document 15); a compound having a methyl group at the 4-position of the coumarin skeleton, and substituents at the 7- and 8-positions (Non-patent document 16); a compound having substituents at all of the 4-, 5-, 6-, 7- and 8-positions of the coumarin skeleton (Non-patent document 17); a compound in which an amide group, ester group or sulfonamide group is directly bound to the coumarin skeleton at the 3-position, and which has a substituent at the 6- or 8-position (Non-patent documents 18 and 19); a compound in which an amide group is directly bound to the coumarin skeleton at the 3-position, and which has a substituent at the 7-position (Patent document 3 and Non-patent document 20); a compound having substituents at the 6- and 7-positions of the coumarin skeleton (Non-patent document 21); a compound having a hydroxy group at the 7-position of the coumarin skeleton, and a nitro group at an appropriate position of the 3-, 6- and 8-positions (Non-patent documents 22 and 23); and a compound having a methoxy or hydroxy group at the 7-position of the coumarin skeleton, a phenyl group at the 3-position, and a substituent at the 4-position.
There have also been reported: a compound having a substituent with a nitrogen atom (diethylamino group, etc.) at the 7-position, a cyano group at the 4-position, and a heteroaryl group at the 3-position (optionally with no substituent at the 4-position) (Non-patent document 32); and a compound having a heteroaryl group at the 3-position, and a methyl group, halogen atom, nitro group, etc. at the 6-, 7- or 8-position (Non-patent document 33). There have also been reported examples of using a compound with a coumarin structure as a ligand for a Pd compound having antitumor activity in cells (Non-patent document 34).
As for compounds which exhibit target protein inhibitory activity, and which are likely to have antitumor activity despite the absence of a report dealing with their antitumor activity, there have been reported coumarin derivatives exhibiting TNFα inhibitory activity (Patent document 4 and Non-patent documents 24 to 28), aromatase inhibitory activity (Non-patent document 29), MEK inhibitory activity (Non-patent document 30), or the like. In compounds mentioned in these reports, the substituents are located at the 3-, 4-, 6- or 7-position of the coumarin skeleton.
As described above, although several coumarin derivatives having antitumor activity are known, few of the compounds exhibit a sufficiently high antitumor activity to put it to practical use as an anticancer drug. Therefore, more practical compounds having sufficiently high antitumor activity are still strongly sought.
Patent document 1: International Publication WO 2000/039120
Patent document 2: International Publication WO 2004/069820
Patent document 3: International Publication WO 2003/024950
Patent document 4: International Publication WO 2002/008217
Patent document 5: International Publication WO 2006/067466
Non-patent document 1: Ansell, J.; Bergqvist, D; Drugs 2004, 64, 1-5
Non-patent document 2: Purohit, A.; Woo, L. W. L.; Chander, S. K.; Newman, S. P.; Ireson, C.; Ho, Y.; Grasso, A.; Leese, M. P.; Potter, B. V. L.; Reed, M. J.; J. Steroid Biochem. Mol. Biol. 2003, 86, 423-432
Non-patent document 3: Lloyd, M. D.; Pederick, R. L.; Natesh, R.; Woo, L. W. L.; Purohit, A.; Reed, M. J.; Acharya, K. R.; Potter, B. V. L.; Biochem. J. 2005, 385, 715-720
Non-patent document 4: Purohit, A.; Woo, L. W. L.; Potter, B. V L.; Reed, M. J.; Cancer Research 2000, 60, 3394-3396
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Non-patent document 6: Woo, L. W. L.; Purohit, A.; Reed, M. J.; Potter, B. V. L.; J. Med. Chem. 1996, 39, 1349-1351
Non-patent document 7: Lopez-Perez, J. L.; Olmedo, D. A.; Olmo, E. D.; Vasquez, Y.; Solis, F N.; Gupta, M. P.; Feliciano, A. S.; J. Nat. Prod. 2005, 68, 369-373
Non-patent document 8: Ito, C.; Itoigawa, M.; Mishina, Y.; Filho, V. C.; Enjo, F.; Tokuda, H.; Nishino, H.; Furukawa, H.; J. Nat. Prod. 2003, 66, 368-371
Non-patent document 9: Chen, Y-C.; Cheng, M-J.; Lee, S-J.; Dixit, A-K.; Ishikawa, T.; Tsai, I-L.; Chen, I-S.; Helv. Chim. Acta 2004, 87, 2805-2811
Non-patent document 10: Lee, K-H.; Chai, H-B.; Tamez, P. A.; Pezzuto, J. M.; Cordell, G. A.; Win, K. K.; Tin-Wa, M.; Phytochemistry 2003, 64, 535-541
Non-patent document 11: Chaturvedula, V. S. P.; Schilling, J. K.; Kingston, D. G. I.; J. Nat. Prod. 2002, 65, 965-972
Non-patent document 12: Madari, H.; Panda, D.; Wilson, L.; Jacobs, R. S.; Cancer Research 2003, 63, 1214-1220
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Non-patent document 14: Baba, M.; Jin, Y.; Mizuno, A.; Suzuki, H.; Okada, Y.; Takasuka, N.; Tokuda, H.; Nishino, H.; Okuyama, T.; Biol. Pharm. Bull. 2002, 25, 244-246
Non-patent document 15: Chen, Y-L.; Wang, T-C.; Tzeng, C-C.; Helv. Chim. Acta 1999, 82, 191-197
Non-patent document 16: Mazzei, M.; Miele, M.; Nieddu, E.; Barbieri, F.; Bruzzo, C.; Alama, A.; Eur. J. Med. Chem. 2001, 36, 915-923
Non-patent document 17: Kimura, S.; Ito, C.; Jyoko, N.; Segawa, H.; Kuroda, J.; Okada, M.; Adachi, S.; Nakahata, T.; Yuasa, T.; Filho, V. C.; Furukawa, H.; Maekawa, T.; Int. J. Cancer 2005, 113, 158-165
Non-patent document 18: Reddy, N. S.; Mallireddigari, M. R.; Cosenza, S. C.; Gumireddy, K.; Bell, S. C.; Reddy, E. P.; Reddy, M. V. R.; Bioorg. Med. Chem. Lett. 2004, 14, 4093-4097
Non-patent document 19: Reddy, N. S.; Gumireddy, K.; Mallireddigari, M. R.; Cosenza, S. C.; Venkatapuram, P.; Bell, S. C.; Reddy, E. P.; Reddy, M. V. R.; Bioorg. Med. Chem. 2005, 13, 3141-3147
Non-patent document 20: Kempen, I.; Papapostolou, D.; Thierry, N.; Pochet, L; Counerotte, S.; Masereel, B.; Foidart, J. M.; Ravaux, M. R.; Noeul, A.; Pirotte, B.; Br. J. Cancer 2003, 88, 1111-1118
Non-patent document 21: Kim, H. H.; Bang, S. S.; Ghoi, J. S.; Han, H.; Kim, I-H.; Cancer Letters 2005, 223, 191-201
Non-patent document 22: Finn, G. J.; Creaven, B. S.; Egan, D. A.; Cancer Letters 2004, 214, 43-54
Non-patent document 23: Finn, G. J.; Creaven, B. S.; Egan, D. A.; Euro. J. Pharmacol. 2003, 481, 159-167
Non-patent document 24: Cheng, J. F.; Chen, M.; Wallace, D.; Tith, S.; Arrhenius, T.; Kashiwagi, H.; Ono, Y.; Ishikawa, A.; Sato, H.; Kozono, T.; Sato, H.; Nadzan, A. M.; Bioorg. Med. Chem. Lett. 2004, 14, 2411-2415
Non-patent document 25: Fries, W.; Mazzon, E.; Sturiale, S.; Giofre, M. R.; Lo Presti, M. A.; Cuzzocrea, S.; Campo, G. M.; Caputi, A. P.; Longo, G.; Sturniolo, G. C.; Life Sci. 2004, 74, 2749-2756
Non-patent document 26: Corsini, E.; Lucchi, L.; Binaglia, M.; Viviani, B.; Bevilacqua, C.; Monastra, G.; Marinovich, M.; Galli, C. L.; Eur. J. Pharmacol. 2001, 418, 231-237
Non-patent document 27: Cuzzocrea, S.; Mazzoln, E.; Bevilaqua, C.; Costanitino, G.; Britti, D.; Mazzullo, G.; De Sarro, A.; Caputi, A. P.; Br. J. Pharmacol. 2000, 131, 1399-1407
Non-patent document 28: Tada, Y.; Shikishima, Y.; Takaishi, Y.; Shibata, H.; Higuti, T.; Honda, G.; Ito, M.; Takeda, Y.; Kodzhimatov, O. K.; Ashurmetov, O.; Ohmnoto, Y.; Phytochemistry 2002, 59, 649-654
Non-patent document 29: Chen, S.; Cho, M.; Karlsberg, K.; Zhou, D.; Yuan, Y. C.; J. Biol. Chem. 2004, 279, 48071-48078
Non-patent document 30: Han, S.; Zhou, V.; Pan, S.; Liu, Y.; Hornsby, M.; McMullan, D.; Klock, H. E.; Haugen, J.; Lesley, S. A.; Gray, N.; Caldwell, J.; Gu, X-J.; Bioorg. Med. Chem. Lett. 2005, 15, 5467-5473
Non-patent document 31: Kulkarni, M. V.; Kulkarni, G. M.; Lin, C-H.; Sun, C-M; Current Medicinal Chemistry 2006, 13, 2795-2818
Non-patent document 32: Lee, S.; Sivakumar, K.; Shin, W-S.; Xie, F.; Wang, Q.; Bioorganic & Medicinal Chemistry Letters 2006, 16, 4596-4599
Non-patent document 33: Vijaya, K. P.; Rajeswar, R. V.; Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry 2005, 44B, 2120-2125
Non-patent document 34: Budzisz, E.; Malecka, M.; Lorenz, I-P.; Mayer, P.; Kwiecien, R. A.; Paneth, P.; Krajewska, U.; Rozalski, M.; Inorganic Chemistry 2006, 45, 9688-9695